Nuffield Department of Medicine, University of Oxford, Oxford, UK.
Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
Genome Med. 2021 Sep 3;13(1):144. doi: 10.1186/s13073-021-00947-2.
The incidence of Gram-negative bloodstream infections (BSIs), predominantly caused by Escherichia coli and Klebsiella species, continues to increase; however, the causes of this are unclear and effective interventions are therefore hard to design.
In this study, we sequenced 3468 unselected isolates over a decade in Oxfordshire (UK) and linked this data to routinely collected electronic healthcare records and mandatory surveillance reports. We annotated genomes for clinically relevant genes, contrasting the distribution of these within and between species, and compared incidence trends over time using stacked negative binomial regression.
We demonstrate that the observed increases in E. coli incidence were not driven by the success of one or more sequence types (STs); instead, four STs continue to dominate a stable population structure, with no evidence of adaptation to hospital/community settings. Conversely in Klebsiella spp., most infections are caused by sporadic STs with the exception of a local drug-resistant outbreak strain (ST490). Virulence elements are highly structured by ST in E. coli but not Klebsiella spp. where they occur in a diverse spectrum of STs and equally across healthcare and community settings. Most clinically hypervirulent (i.e. community-onset) Klebsiella BSIs have no known acquired virulence loci. Finally, we demonstrate a diverse but largely genus-restricted mobilome with close associations between antimicrobial resistance (AMR) genes and insertion sequences but not typically specific plasmid replicon types, consistent with the dissemination of AMR genes being highly contingent on smaller mobile genetic elements (MGEs).
Our large genomic study highlights distinct differences in the molecular epidemiology of E. coli and Klebsiella BSIs and suggests that no single specific pathogen genetic factors (e.g. AMR/virulence genes/sequence type) are likely contributing to the increasing incidence of BSI overall, that association with AMR genes in E. coli is a contributor to the increasing number of E. coli BSIs, and that more attention should be given to AMR gene associations with non-plasmid MGEs to try and understand horizontal gene transfer networks.
革兰氏阴性菌血流感染（BSI）的发病率持续上升，主要由大肠杆菌和克雷伯菌引起，但原因尚不清楚，因此难以设计有效的干预措施。
本研究对牛津郡（英国）十多年来的 3468 例未选择的分离株进行了测序，并将这些数据与常规收集的电子医疗记录和强制性监测报告相关联。我们对临床相关基因进行了基因组注释，对比了这些基因在种内和种间的分布，并使用堆积负二项式回归比较了随时间的发病趋势。
我们证明，大肠杆菌发病率的上升不是由一个或多个序列型（ST）的成功引起的；相反，四个 ST 继续主导一个稳定的种群结构，没有证据表明它们适应了医院/社区环境。相反，在克雷伯菌属中，大多数感染是由零星的 ST 引起的，除了局部耐药暴发菌株（ST490）。在大肠杆菌中，毒力基因高度受 ST 结构的影响，但在克雷伯菌属中并非如此，它们存在于各种 ST 中，并且在医疗保健和社区环境中同样存在。大多数临床上高度毒力（即社区发病）的克雷伯菌 BSI 没有已知的获得性毒力基因座。最后，我们展示了一个多样化但主要限于属的可移动基因组，其中抗生素耐药（AMR）基因和插入序列之间存在密切关联，但通常与质粒复制子类型无关，这与 AMR 基因的传播高度依赖于较小的移动遗传元件（MGEs）一致。
我们的大型基因组研究突出了大肠杆菌和克雷伯菌 BSI 的分子流行病学的显著差异，并表明，没有单一的特定病原体遗传因素（如 AMR/毒力基因/序列型）可能导致 BSI 的总体发病率上升，大肠杆菌中 AMR 基因的关联是导致大肠杆菌 BSI 数量增加的一个因素，并且应该更加关注 AMR 基因与非质粒 MGEs 的关联，以试图了解水平基因转移网络。
